Meta- and Gene Set Analysis of Stomach Cancer Gene Expression Data

  • Kim, Seon-Young (Human Genomics Laboratory, Genome Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Jeong-Hwan (Human Genomics Laboratory, Genome Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee, Heun-Sik (Human Genomics Laboratory, Genome Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Noh, Seung-Moo (Department of General Surgery, College of Medicine, Chungnam National University) ;
  • Song, Kyu-Sang (Department of Pathology, College of Medicine, Chungnam National University) ;
  • Cho, June-Sik (Department of Diagnostic Radiology, College of Medicine, Chungnam National University) ;
  • Jeong, Hyun-Yong (Department of Internal Medicine, College of Medicine, Chungnam National University) ;
  • Kim, Woo Ho (Department of Pathology, Seoul National University College of Medicine) ;
  • Yeom, Young-Il (Human Genomics Laboratory, Genome Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Nam-Soon (Human Genomics Laboratory, Genome Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Sangsoo (National Genome Information Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Yoo, Hyang-Sook (The Center for Functional Analysis of Human Genome, 21st Century Frontier R&D Program, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Yong Sung (Human Genomics Laboratory, Genome Research Center, Korea Research Institute of Bioscience and Biotechnology)
  • Received : 2007.01.30
  • Accepted : 2007.05.07
  • Published : 2007.10.31

Abstract

We generated gene expression data from the tissues of 50 gastric cancer patients, and applied meta-analysis and gene set analysis to this data and three other stomach cancer gene expression data sets to define the gene expression changes in gastric tumors. By meta-analysis we identified genes consistently changed in gastric carcinomas, while gene set analysis revealed consistently changed biological themes. Genes and gene sets involved in digestion, fatty acid metabolism, and ion transport were consistently down-regulated in gastric carcinomas, while those involved in cellular proliferation, cell cycle, and DNA replication were consistently up-regulated. We also found significant differences between the genes and gene sets expressed in diffuse and intestinal type gastric carcinoma. By gene set analysis of cytogenetic bands, we identified many chromosomal regions with possible gross chromosomal changes (amplifications or deletions). Similar analysis of transcription factor binding sites (TFBSs), revealed transcription factors that may have caused the observed gene expression changes in gastric carcinomas, and we confirmed the overexpression of one of these, E2F1, in many gastric carcinomas by tissue array and immunohistochemistry. We have incorporated the results of our meta- and gene set analyses into a web accessible database (http://human-genome.kribb.re.kr/stomach/).

Keywords

Acknowledgement

Supported by : Ministry of Science and Technology in Korea

References

  1. Aggarwal, A., Guo, D. L., Hoshida, Y., Yuen, S. T., Chu, K. M., et al. (2006) Topological and functional discovery in a gene coexpression meta-network of gastric cancer. Cancer Res. 66, 232−241
  2. Bignell, G. R., Huang, J., Greshock, J., Watt, S., Butler, A., et al. (2004) High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res. 14, 287−295
  3. Boussioutas, A., Li, H., Liu, J., Waring, P., Lade, S., et al. (2003) Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res. 63, 2569−2577
  4. Calcagno, D. Q., Leal, M. F., Taken, S. S., Assumpcao, P. P., Demachki, S., et al. (2005) Aneuploidy of chromosome 8 and C-MYC amplification in individuals from northern Brazil with gastric adenocarcinoma. Anticancer Res. 25, 4069− 4074
  5. Chen, X., Leung, S. Y., Yuen, S. T., Chu, K. M., Ji, J., et al. (2003) Variation in gene expression patterns in human gastric cancers. Mol Biol Cell. 14, 3208−3215
  6. Choi, J. K., Yu, U., Kim, S., and Yoo, O. J. (2003) Combining multiple microarray studies and modeling interstudy variation. Bioinformatics. 19 Suppl 1, i84−90 https://doi.org/10.1093/bioinformatics/btg026
  7. Crawley, J. J. and Furge, K. A. (2002) Identification of frequent cytogenetic aberrations in hepatocellular carcinoma using gene-expression microarray data. Genome Biol. 3, RESEARCH0075
  8. Dicken, B. J., Bigam, D. L., Cass, C., Mackey, J. R., Joy, A. A., et al. (2005) Gastric adenocarcinoma: review and considerations for future directions. Ann. Surg. 241, 27−39
  9. Diehn, M., Sherlock, G., Binkley, G., Jin, H., Matese, J. C., et al. (2003) SOURCE: a unified genomic resource of functional annotations, ontologies, and gene expression data. Nucleic Acids Res. 31, 219−223
  10. Do, J. H. and Choi, D. K. (2006) Normalization of microarray data: single-labeled and dual-labeled arrays. Mol. Cells. 22, 254−261
  11. Futreal, P. A., Coin, L., Marshall, M., Down, T., Hubbard, T., et al. (2004) A census of human cancer genes. Nat. Rev. Cancer 4, 177−183
  12. Grade, M., Ghadimi, B. M., Varma, S., Simon, R., Wangsa, D., et al. (2006) Aneuploidy-dependent massive deregulation of the cellular transcriptome and apparent divergence of the Wnt/beta-catenin signaling pathway in human rectal carcinomas. Cancer Res. 66, 267−282
  13. Grade, M., Hormann, P., Becker, S., Hummon, A. B., Wangsa, D., et al. (2007) Gene expression profiling reveals a massive, aneuploidy-dependent transcriptional deregulation and distinct differences between lymph node-negative and lymph nodepositive colon carcinomas. Cancer Res. 67, 41−56
  14. Grutzmann, R., Boriss, H., Ammerpohl, O., Luttges, J., Kalthoff, H., et al. (2005) Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes. Oncogene 24, 5079−5088
  15. Hasegawa, S., Furukawa, Y., Li, M., Satoh, S., Kato, T., et al. (2002) Genome-wide analysis of gene expression in intestinaltype gastric cancers using a complementary DNA microarray representing 23,040 genes. Cancer Res. 62, 7012−7017
  16. Hippo, Y., Taniguchi, H., Tsutsumi, S., Machida, N., Chong, J. M., et al. (2002) Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res. 62, 233− 240
  17. Huang, J., Wei, W., Zhang, J., Liu, G., Bignell, G. R., et al. (2004) Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum. Genomics 1, 287−299
  18. Inoue, H., Matsuyama, A., Mimori, K., Ueo, H., and Mori, M. (2002) Prognostic score of gastric cancer determined by cDNA microarray. Clin. Cancer Res. 8, 3475−3479
  19. Jinawath, N., Furukawa, Y., Hasegawa, S., Li, M., Tsunoda, T., et al. (2004) Comparison of gene-expression profiles between diffuse- and intestinal-type gastric cancers using a genomewide cDNA microarray. Oncogene 23, 6830−6844
  20. Kim, B., Bang, S., Lee, S., Kim, S., Jung, Y., et al. (2003) Expression profiling and subtype-specific expression of stomach cancer. Cancer Res. 63, 8248−8255
  21. Kim, N. S., Hahn, Y., Oh, J. H., Lee, J. Y., Oh, K. J., et al. (2004) Gene cataloging and expression profiling in human gastric cancer cells by expressed sequence tags. Genomics 83, 1024−1045
  22. Kim, S. Y. and Volsky, D. J. (2005) PAGE: Parametric Analysis of Gene set Enrichment. BMC Bioinformatics 6, 144 https://doi.org/10.1186/1471-2105-6-144
  23. Koizumi, Y., Tanaka, S., Mou, R., Koganei, H., Kokawa, A., et al. (1997) Changes in DNA copy number in primary gastric carcinomas by comparative genomic hybridization. Clin. Cancer Res. 3, 1067−1076
  24. Lauren, P. (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 64, 31−49
  25. Lee, H. J., Yang, H. K., and Ahn, Y. O. (2002) Gastric cancer in Korea. Gastric Cancer. 5, 177−182
  26. Lee, H. S., Lee, H. K., Kim, H. S., Yang, H. K., and Kim, W. H. (2003) Tumour suppressor gene expression correlates with gastric cancer prognosis. J. Pathol. 200, 39−46
  27. Meireles, S. I., Cristo, E. B., Carvalho, A. F., Hirata, R., Jr., Pelosof, A., et al. (2004) Molecular classifiers for gastric cancer and nonmalignant diseases of the gastric mucosa. Cancer Res. 64, 1255−1265
  28. Norsett, K. G., Laegreid, A., Midelfart, H., Yadetie, F., Erlandsen, S. E., et al. (2004) Gene expression based classification of gastric carcinoma. Cancer Lett. 210, 227−237
  29. Oien, K. A., Vass, J. K., Downie, I., Fullarton, G., and Keith, W. N. (2003) Profiling, comparison and validation of gene expression in gastric carcinoma and normal stomach. Oncogene 22, 4287−4300
  30. Oue, N., Hamai, Y., Mitani, Y., Matsumura, S., Oshimo, Y., et al. (2004) Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res. 64, 2397−2405
  31. Rhodes, D. R., Barrette, T. R., Rubin, M. A., Ghosh, D., and Chinnaiyan, A. M. (2002) Meta-analysis of microarrays: interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer. Cancer Res. 62, 4427− 4433
  32. Rhodes, D. R., Yu, J., Shanker, K., Deshpande, N., Varambally, R., et al. (2004a) Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc. Natl. Acad. Sci. USA 101, 9309−9314
  33. Rhodes, D. R., Yu, J., Shanker, K., Deshpande, N., Varambally, R., et al. (2004b) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1−6
  34. Rhodes, D. R., Kalyana-Sundaram, S., Mahavisno, V., Barrette, T. R., Ghosh, D., et al. (2005) Mining for regulatory programs in the cancer transcriptome. Nat. Genet. 37, 579−583
  35. Schena, M., Shalon, D., Davis, R. W., and Brown, P. O. (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467−470 https://doi.org/10.1126/science.270.5235.470
  36. Schlemper, R. J., Kato, Y., and Stolte, M. (2001) Review of histological classifications of gastrointestinal epithelial neoplasia: differences in diagnosis of early carcinomas between Japanese and Western pathologists. J. Gastroenterol. 36, 445−456
  37. Segal, E., Friedman, N., Koller, D., and Regev, A. (2004) A module map showing conditional activity of expression modules in cancer. Nat. Genet. 36, 1090−1098
  38. Segal, E., Friedman, N., Kaminski, N., Regev, A., and Koller, D. (2005) From signatures to models: understanding cancer using microarrays. Nat. Genet. 37 Suppl, S38−45
  39. Storey, J. D. and Tibshirani, R. (2003) Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440−9445
  40. Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545- 15550
  41. Tan, P. K., Downey, T. J., Spitznagel, E. L., Jr., Xu, P., Fu, D., et al. (2003) Evaluation of gene expression measurements from commercial microarray platforms. Nucleic Acids Res. 31, 5676−5684
  42. Tay, S. T., Leong, S. H., Yu, K., Aggarwal, A., Tan, S. Y., et al. (2003) A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes. Cancer Res. 63, 3309−3316
  43. Troyanskaya, O., Cantor, M., Sherlock, G., Brown, P., Hastie, T., et al. (2001) Missing value estimation methods for DNA microarrays. Bioinformatics 17, 520−525
  44. Weiss, M. M., Kuipers, E. J., Postma, C., Snijders, A. M., Siccama, I., et al. (2003) Genomic profiling of gastric cancer predicts lymph node status and survival. Oncogene 22, 1872− 1879
  45. Weiss, M. M., Kuipers, E. J., Postma, C., Snijders, A. M., Pinkel, D., et al. (2004) Genomic alterations in primary gastric adenocarcinomas correlate with clinicopathological characteristics and survival. Cell Oncol. 26, 307−317
  46. Yamashita, Y., Nishida, K., Okuda, T., Nomura, K., Matsumoto, Y., et al. (2005) Recurrent chromosomal rearrangements at bands 8q24 and 11q13 in gastric cancer as detected by multicolor spectral karyotyping. World J. Gastroenterol. 11, 5129−5135
  47. Yang, Y. H., Dudoit, S., Luu, P., Lin, D. M., Peng, V., et al. (2002) Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res. 30, e15 https://doi.org/10.1093/nar/30.4.e15
  48. Yang, S. H., Seo, M. Y., Jeong, H. J., Jeung, H. C., Shin, J., et al. (2005) Gene copy number change events at chromosome 20 and their association with recurrence in gastric cancer patients. Clin. Cancer Res. 11, 612−620
  49. Zheng, L., Wang, L., Ajani, J., and Xie, K. (2004) Molecular basis of gastric cancer development and progression. Gastric Cancer 7, 61−77